Bicalutamide is the generic name for the compound N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulphonyl]-2-hydroxy-2-methyl propanamide and is represented by the formula (I)

Bicalutamide and related various acyl anilides have been disclosed in U.S. Pat. No. 4,636,505 as pharmaceutically active compounds possessing anti-androgenic activity useful in the treatment of prostate cancer. The pharmaceutical product derived from Bicalutamide is approved worldwide under the brand name Casodex.
Process for preparing Bicalutamide has been reported in U.S. Pat. No. 4,636,505 issued to ICI and Tucker et. al. in J. med. Chem, 31, 9-954-959 (1988) by reacting 3-Trifluoromethyl-4-cyanoaniline of Formula (IV) with methacryloyl chloride of Formula (III) followed by epoxidation of the resultant N-(3-trifluoromethyl-4-cyanophenyl)methacrylamide of Formula (V). The epoxide ring is opened with 4-fluorothiophenol and subsequent conversion to sulfone resulted in Bicalutamide of Formula (I).
Bicalutamide is a non-steroidal pharmaceutically active agent possessing antiandrogenic properties, generally used in treatment of prostate cancer i.e. for androgen deprivation treatment, although other androgen dependent conditions may also be treated. Bicalutamide is commercially available in a pharmaceutical composition as a racemate under the brand name Casodex (Astra-Zeneca). The stereoisomer of Bicalutamide has been proposed in U.S. Pat. No. 5,985,868 as being more beneficial than the racemate. Various other methods for the preparation for Bicalutamide are disclosed in WO0224638, U.S. Pat. No. 6,479,692, WO02100339, US20030073742 and US20030045742.
Though there are several methods known in the art for making N-[4-Cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulphonyl]-2-hydroxy-2-methyl propanamide i.e Bicalutamide from its precursor (VII) i.e. N-[4-cyano-3-(trimethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-hydroxy-2-methyl propanamide (VII) by oxidation, however, involves the use of different oxidizing agents including various peracids.
WO0224638 discloses the above oxidation using 30% H2O2 in presence of trifluoro acetic anhydride in methylene dichloride (CH2Cl2) at 25° C. to 30° C.
WO0353920 claims oxidation process of N-[4-cyano-3-(trimethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-hydroxy-2-methyl propanamide (VII) using H2O2/Sodium tungstate/Phenyl phosphoric acid/TBAB/Ethyl acetate.
EP0100172, WO0134563, WO02100339 and Tucker et al in J. Med. Chem. 954-959 disclose the oxidation of N-[4-cyano-3-(trimethyl)phenyl]-3-[(4-fluorophenyl)thio]-2-hydroxy-2-methyl propanamide(VII) using m-chloro perbenzoic acid (m-CPBA) in chlorinated solvent, that requires longer durations for reaction. Thus, the process disclosed in the prior art not only involves the use of expensive reagents and chlorinated solvents, but also their handling and risk concerns while handing them at commercial scales. Chlorinated solvents are particularly known to be harmful to humans with a suggested possibility of being carcinogenic and also produce dioxin during disposal. Further solvents like CH2Cl2 involves higher cost of disposal due to corrosion during incineration.
Further the chemical risk reduction policy, “Green Chemistry” is gaining attention and industrially feasible environment friendly chemical reactions (avoiding, as far as possible, the use of harmful chemicals and developing reactions which do not as far as possible discharge these) are becoming an essential feature in research. The above-mentioned reaction using CH2Cl2 as organic solvent is from this point of view not suited for the method of preparation of the desirable Bicalutamide.
Besides being an expensive reagent, MCPBA is a highly explosive material and therefore not suitable for industrial level productions.
One such synthesis of Bicalutamide without the use of m-CPBA is published in WO0100608, which involves the use of an aqueous solution of H2O2 and the compound is oxidized in acetic or formic acid and is considered as an excellent industrial method environmentally and economically for conversion of Formula (VII) to Formula (I). However in this method, both polar and non-polar impurities are formed which are not reduced during purification. Further this method also has a step involving use of halogenated organic solvent (e.g. 1,1,1-trichloro ethane) for the synthesis of (VI) and so cannot be considered environmentally friendly.
Further in WO0224638, H2O2 aqueous solution is added to compound of Formula (VII) and the mixture after cooling to −55° C., anhydrous trifluoro acetic acid (TFA) is added to the mixture to get Bicalutamide. But in this method the use of explosive TFA as reagent and the need for cooling during the addition of TEA makes the method uneconomical. Further anhydrous TFA is corrosive and hygroscopic.
WO03053920 has claimed the process of oxidation using H2O2/Sodium tungstate/Phenyl phosphoric acid/TBAB/Ethyl acetate in good yield. Here the large excess of H2O2 (3 to 6 equivalents) per mole equivalent of the compound of Formula (VII) and use of large quantity of Sodium tungstate or phenyl phosphoric acid, 0.5 to 5% quantity of compound. Further removal of Sodium tungstate and Phenyl phosphoric acid from the reaction mixture is tedious.
Despite the aforementioned various disclosures mentioning various processes, there still remains a need for new economically viable process and amenable to industrial scale up.
Hence, the present specification is aimed to provide an improved process for the synthesis of Bicalutamide in high yield and purity, which involves the use of inexpensive, non-hazardous and easily available oxidizing agent.